Monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals are responsible for acute synovial inflammation but also contribute to cartilage degradation and bone lesions within the joint. They activate multiple signal transduction pathways leading to cell activation and recruitment. Some signalling pathways are activated by both types of crystals, and other pathways may only be activated by one type depending on cell type, namely neutrophils, monocytes, macrophages, synovial fibroblasts, endothelial cells and chondrocytes. Cascades of activated proteins involve cytoplasmic membrane related proteins (FAK complex, Src family tyrosine kinases), but also MAPK and NF-kB pathways, leading to NO, prostanoid and cytokine production, and protease activation. This review will also focus on potential therapeutic targets related to cellular signalling in MSU and CPPD crystal-induced inflammation.